ApoB is essential to life yet excess apoB100 or apoB48 is atherogenic and associated with increased risk of cardiovascular disease. We identified and cloned a new, unique receptor (R) for dietary triglyceride-rich lipoproteins (TGRLP), the apoB48 R. It is constitutively expressed on monocyte-macrophages (MM), including human atherosclerotic foam cells and bone marrow precursors, and endothelial cells (ECs), cells intimately involved in hemostasis and atherothrombogenesis as well as hemopoiesis, immune function and tissue nutrition. Although we have documented that the apoB48 R binds to apoB48, major questions remain on the precise mechanism(s) of binding and why normal VLDL and LDL have low affinity for this R--which microdomain of apoB48 is necessary for R binding and how the other apoB regions, apoproteins, and lipid constituents modulate binding of lipoproteins to this R. Our published and preliminary data support the hypotheses that (1) an apoB48 microdomain that is required for binding is at or near the lipoprotein lipase binding site, is not releaseable by trypsin, is not in a heparin binding domain, and is masked in normal VLDL and LDL; (2) apoB48 R binding affinity is greater in large particles (Sf greater than 100) than in small particles (Sf less than 100); and (3) apoE inhibits binding to the apoB48 R. This ensures sufficient uptake of larger nutrient-rich (lipids and lipid-soluble vitamins) dietary particles by cells responsible for tissue nutrition, immune function and hemopoiesis, cells with high nutritional requirements, and directs smaller apoB lipoproteins to the liver, as observed in vivo. We propose multiple approaches to define the R-binding apoB48 microdomain (Aim 1) and to define modulators of this interaction (Aim 2), using native, modified, and model lipoproteins, monoclonal antibodies, C-terminal truncated apoB, molecularly engineered apoB mutant constructs, and cell and ligand blotting studies. Knowledge of the basic biochemical determinants and molecular mechanisms that govern the interactions of TGRLP with the apoB48 R are crucial to meaningful intervention to prevent excess, atherothrombogenic uptake by this route while preserving sufficient nutrient uptake or, conversely, to enhance uptake in subjects with multiple pathologies due to defective or deficient apoB.